This invention relates to a process for the preparation of penam and cephem derivatives by reacting a phosphite amide of the general formula: ##STR1## wherein X represents a group of the general formula: ##STR2## wherein the carbon atom adjacent to the COOR.sup.1 group is connected to the nitrogen atom, R.sup.1 represents a substituted or non-substituted alkyl or aralkyl group, or a metal organic group, R.sup.2 represents hydrogen, an acetoxy group, or --S--Het, wherein Het represents a heterocyclic group, and Z represents a group having the formula: ##STR3## wherein R.sup.3 represents an alkyl group, R.sup.4 and R.sup.5 are the same or different, and each represent an alkyl group, n represents 1 or 2, m represents 0, 1, or 2, with an acyl halide in an aprotic solvent.
The specification of Belgian Pat. No. 809,110 and the cognate British patent applications Nos. 12788/75 and 26826/75 disclose a process for the preparation of penam and cephem derivatives by reacting a phosphite amide of 6-aminopenicillanic acid or 7-aminocephalosporanic acid with an acyl halide in an aprotic solvent. This reaction produces penam or cephem compounds in high yields. The reaction is proton catalysed, and the reaction rate may be controlled by varying the proton concentration in the reaction medium, for example by adding as a proton source varying amounts of an acid addition salt of a weak tertiary amine optionally in admixture with the weak tertiary amine itself. Examples of such amines are pyridine and N,N-dimethylaniline and examples of acid addition salts are hydrochlorides. The overall reaction proceeds with elimination of a phosphite halide, as exemplified in the following reaction scheme for the synthesis of the trimethylsilyl ester of amipicillin: ##STR4##
Phosphite halides, such as the compound having the formula A, while quite stable under aprotic conditions, react with hydroxylic reagents like water and alcohols. During synthesis, therefore, hydroxyl groups and similar substituents should be properly protected. Problems may also arise when a hydrolytic step is included in a synthesis of such sensitive compounds as penicillins and cephalosporins, unless the violent reaction between the phosphite halide and water is adequately controlled. Surprisingly, it has now been found that these obstacles may be overcome by adding a phosphite halide scavenger to the reaction mixture.